Several drugs that interfere with
sterol metabolism have been associated with hyperkeratosis in man. We found that
20,25-diazacholesterol (30 to 60 mg/kg/day), administered to hairless mice that were otherwise given normal laboratory chow and water ad libitum, consistently produced
ichthyosis after 6 to 9 weeks, an effect that was reversible with removal of
drug or with coadministration of a high
cholesterol diet. Scaling was most pronounced over the tail, but some stratum corneum retention was noted over the entire skin surface. As measured in frozen sections, stratum corneum thickness was three to 10 times thicker in treated animals than in either controls or revertants.
Oil red O-stained frozen sections and freeze fracture replicas revealed decreased stratum corneum
membrane lipids in the diazacholesterol-treated animals, but this finding was not specific, since a similar deficit was found in control and revertant tail stratum corneum but not in the stratum corneum from other sites. Stratum corneum
lipid extracts revealed reduced total free
sterols, reduced
cholesterol, accumulation of several normally absent
sterol precursors, and increased
glycosphingolipids on thin-layer chromatography and high pressure liquid chromatography. In summary, we describe a syndrome of
drug-induced
ichthyosis in hairless mice that parallels the
drug-induced syndrome in man. This syndrome is reversible and accompanied by distinctive abnormalities in cutaneous
sterol metabolism. The diazacholesterol model may further our understanding of the pathogenesis of human keratinizing disorders and may provide a valuable analogue for testing new forms of
therapy, such as
retinoids, for scaling
dermatoses.